The Laboratory is investigating the use of high resolution two dimensional electrophoresis and high sensitivity protein detection methods as a "non-biased" diagnostic tool. This non-biased diagnostic tool can permit the quantitative visualization of more than a thousand protein gene products in almost any tissue or body fluid sample. It is Likely that some of these will be affected by disease states. The patterns of qualitative and quantitative alterations may provide new diagnostic capabilities and insights into the underlying pathophysiological processes. Proteins which appear to be abnormal in disease states can often be sequenced and identified by comparisons with existing databases or partial sequences can be used as an aid in isolating the gene of origin. The development of new methods including: crosslinking agents, electrophoretic, and silver staining protocols by the Laboratory have increased the resolution and reproducibility of the electrophoretic techniques. The Laboratory is expanding its studies of clinically relevant diseases. Applications of these methodologies in studies of protein patterns in spinal fluid have Led to the discovery of diagnostic proteins for Creutzfeldt-Jakob disease, Parkinson's disease, and the presence of two abnormal proteins in more than 1/3 of the schizophrenic patients in our studies. Diagnostic proteins have also been found with these technoLogies in a number of other diseases by other groups, including certain forms of leukemia. The Laboratory pLans to expand our examination of disease and physiological states. The Laboratory is currently isolating and sequencing some of the proteins which appear to be of interest.